Intra-hepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor outcomes that have improved only marginally in recent decades. Other types of adult malignancies where sub-groups of patients can be identified, often by particular feature of their cancer such as a genetic change, have benefitted from tailored therapies in which treatment is used specific to that disease subtype. Such strategies have not been developed for cholangiocarcinoma. Moreover, there is a poor understanding of genetic and molecular underlying this cancer type, limiting approaches toward early detection and prevention. Research has been hampered by a relatively few human tumor cell lines and animal model systems. In response to these roadblocks we a) conducted extensive work on the genetics of this disease and b) developed a new mouse model based on the human disease. Our genetic studies established two distinct subsets of disease and the new model displays many characteristic features of the human disease. Furthermore, the model suggests that early changes in the liver that are observed in humans may be precursor steps that lead to IHCC. We have also used this model to successfully test a novel treatment approach using a well-known drug, chloroquine, for a subset of these tumors. Based on these findings, we will use human tissues and animal models to answer 1) where in the liver does this tumor emerge from and what are the earliest genetic changes, 2) how do other genetic changes influence tumor behavior, and 3) how does the tumor subtype affect the ability of the drug chloroquine to stop its growth. Given the severity of the disease and the immediate availability of this drug for clinical use these studies could lead to an immediate positive effect for patients with the disease. Moreover, many new models of disease and reagents produced by this study will enable others focused on research in this disease to make forward progress.